Molecular biological techniques have revealed the existence of several subtypes of the dopamine receptor. The dopamine D.sub.1 receptor subtype has been shown to occur in at least two discrete forms. Two forms of the D.sub.2 receptor subtype, and at least one form of the D.sub.3 receptor subtype, have also been discovered. More recently, the D.sub.4 (Van Tol et al., Nature (London), 1991, 350, 610) and D.sub.5 (Sunahara et al., Nature (London), 1991, 350, 614) receptor subtypes have been described.
The "dopamine hypothesis" of schizophrenia predicts an increased activity of dopamine neurotransmission in the brain. This hypothesis is supported by observations that drugs, such as amphetamine and cocaine, which indirectly stimulate the endogenous dopamine system by a dopamine release and uptake inhibition are capable of eliciting a psychosis resembling acute paranoid schizophrenia. The fact that classical antipsychotic drugs produce their therapeutic effect by blocking central dopamine D.sub.2 receptors also lends credence to the "dopamine hypothesis". It is however a serious drawback to the classical anti-psychotic drugs that the blockage of dopamine D.sub.2 receptors also leads to extrapyrimidal side-effects (EPS).
Clozapine is the only neuroleptic agent that improves the "positive" and "negative" symptoms of schizophrenia without producing EPS. The mechanism of action of Clozapine remains elusive, but has been proposed to be due, in part to a greater blockade of dopamine D.sub.4 receptors compared to D.sub.2 receptors, and also to a blockade of serotonin 5-HT2A receptors. It is considered that compounds which can interact selectively with the dopamine D.sub.4 receptor subtype, whilst having a less pronounced action at the D.sub.2 subtype will be less prone to give the side-effects associated with classical antipsychotic drugs while maintaining a beneficial level of antipsychotic activity.
The compounds of the present invention are antagonists of the dopamine D.sub.4 receptor they are predicted to be useful for the treatment of psychotic disorders such as schizophrenia.
Dopamine receptors are important for many functions in the animal body. For example, altered functions of these participate in the genesis of psychosis, addiction, sleep, feeding, learning, memory, sexual behaviour, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events, compounds that act preferentially on the dopamine D.sub.4 receptor may exert a wide range of therapeutic effects in humans. The compounds of the present invention may therefore also be useful for the treatment of conditions such as sleep disorders, sexual disorders, gastrointestinal disorders, various forms of psychosis (affective psychosis, nonorganic psychosis), personality disorders, psychiatric mood disorders, conduct and impulse disorders, polydipsia, bipolar disorders, dysphoric mania, anxiety and related disorders, obesity, emesis, learning disorders, memory disorders, Parkinson's disease, depression, neuroleptic malignant syndrome, hypothalamic pituitary disorders, congestive heart failure, chemical dependencies such as drug and alcohol addictions, vascular and cardiovascular disorders, ocular disorders (including glaucoma), dystonia, tardive dyskinesia, Gilles De La Tourette's Syndrome and other hyperkinesias, dementia, ischaemia, movement disorders such as akathesia, hypertension and diseases caused by a hyperactive immune system such as allergies and inflammation.